Академический Документы
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Kunio Kawamura
Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
I. PURPOSE OF VALIDATION
High-quality water and air are essential for the manufacture of pharmaceuticals.
Water is the most commonly used raw material in pharmaceutical manufactur-
ing; it is indirectly used in the manufacture of all dosage forms for cleaning
manufacturing equipment, and is also used as a major component which consti-
tutes injectable products. It is the one raw material that is usually processed by
the pharmaceutical manufacturer prior to use because it cannot be used as sup-
plied by the vendor. Water should be regarded as one of major raw materials for
the manufacture of pharmaceuticals whether or not it remains as a component of
the finished dosage form or is eliminated during the manufacturing process.
Water is thus an important raw material in GMP and in validating the manufac-
turing process.
Air supplied to the pharmaceutical manufacturing area or the air in the
environment of the pharmaceutical manufacturing area always contacts with
pharmaceuticals, and the quality of air influences the quality of the pharmaceuti-
cals manufactured, particularly in their cleanliness, particulates, and microbial
quality. Temperature and humidity in the manufacturing environment also influ-
ence the quality of the pharmaceuticals manufactured.
The importance of air quality and air handling system are described in
CFR 211-46 as part of GMP.
The USP identifies several grades of water that are acceptable for use in
pharmaceuticals, and also defines the quality of the environment or the quality
of air for the manufacturing of pharmaceuticals according to its criticality.
3. Steps of Validation
Validation plans for water and air systems typically include the following steps
(Fig. 1):
1. Establishing standards for quality attributes of water and air to man-
ufacture pharmaceuticals.
2. Defining systems and subsystems suitable to produce the desired
water and air by considering the quality grades of water and air.
3. Designing equipment, controls, and monitoring technologies.
4. Establishing standards for operating parameters of the selected
equipment of the system.
5. Developing an IQ stage consisting of instrument calibrations, inspec-
tions to verify that the drawings accurately depict the as-built config-
uration of the system, and special tests to verify that the installation
meets the design requirements. These items include pipe and instru-
ment drawings, air pressure differentials, air velocities, and airflow
patterns.
Microbial Particulate
Inorganics control Microbial limit matter Endotoxin
The manufacturing method and distribution system also have a close rela-
tion with the construction design of facilities and equipment.
1. Selection of the most suitable quality grade of water for its intended use.
2. Determination of the water manufacturing system elements, including
facility and equipment.
3. Design of water manufacturing system, including the design of system
equipment.
4. After construction of the water system is completed based on its de-
sign, the system has to be scrutinized as to whether it has been built
to design specification or not.
5. Dead Legs
Dead legs pose two problems for CIP. First, cleaning fluids must be able to
flush out trapped gas pockets in order to wet all the piping surfaces in the dead
legs. Second, fresh cleaning fluid must flush the dead leg to maintain rapid
cleaning rates. Dead legs should not be greater in length than six diameters (6D)
of the unused portion measured from the axis of the pipe in use.
6. Valves
The most commonly used valves in process piping systems for PW and WFI
used for pharmaceutical manufacturing are diaphragm valves. This is because
they are easily CIP-cleanable and provide complete containment of in-process
materials. Diaphragm valves are limited in the ways they may be installed for
free drainage; they sometimes are prone to leakage and they have a relatively
high pressure drop as compared with other types of valves.
For situations in which complete containment is not required, “plunger-
type” compression valves of hygienic design may be used. These have several
advantages over diaphragm valves regarding installation and operation but they
do not provide complete containment.
Ball and butterfly valves are also commonly used in water treatment sys-
tems. Diaphragm valves should be used downstream from the unit that removes
dissolved solids (reverse osmosis unit or deionizer), however, because of their
inherent ease of sanitation.
7. Pumps
Pumps should be of sanitary design with seals that prevent contamination of the
water. Pumps moving water for manufacturing or final rinsing, water for cooling
the drug product after sterilization, and in-process or drug product solutions
shall be designed to utilize water for injection as a lubricant for the seals. Sev-
eral types of CIP-cleanable pumps are commonly used in water systems or phar-
maceutical manufacturing processes. These include centrifugal, rotary lobe, peri-
staltic, and diaphragm pumps, of which all but the centrifugal pump provide
positive displacement.
8. In-Line Instrumentation
In-line instruments or sensors are necessary components for automated pro-
cesses. For ease of cleaning, sensors should be chosen that directly mount onto
vessel nozzles or piping tees with minimum dead leg distances. Also, the instru-
9. Pressure Gauges
Sanitary diaphragm-style pressure gauges should be used when possible, as they
are very cleanable. When pressure gauges are installed in process piping, the
diameter should be less than 6D.
11. Distillation
Distillation equipment is used to produce USP WFI-quality water. The distilla-
tion process removes dissolved solids not otherwise removed by deionizers or
RO units.
The chemical quality of the steam supplied to the still must be controlled
to prevent recontamination of the distillate. Also, the condenser must be of a
double-tube design to prevent condenser coolant from coming into direct contact
with the distallate, thereby causing recontamination.
Separation of mists by the distillation process is important to remove the
endotoxin or other contaminant. Distillators have their own upper limits of
throughput capacity. Usually the more the amount of water generated at the unit
period, the more the conductivity increases at the range of maximum capacity.
This means that the purity of the water becomes worse.
12. Filters
Final filters of water for injectable products may not be used at any point in the
piping system of water for manufacturing or final rinse.
Water storage tank vent filters must be equipped with a sterilizing air filter
in order to prevent the air, which displaces water drawn from the tank, from
microbiologically contaminating the water. The filter must be hydrophobic in
order to prevent condensation from blinding the filter and preventing air entry
or escape from the tank. It also must have a mean porosity of less than 1 µm.
Water filters are used in various locations in water treatment systems for
two basic purposes: removal of undissolved solids, some of which are added to
the water by various components of the water treatment system, and removal of
16. Wastewater
Waste liquids shall be introduced to sewers through trapped drains. Drains from
equipment shall be designed with an atmospheric break to prevent back-
siphonage.
All stills and tanks holding liquid requiring microbial control shall have
air vents with non-fiber-releasing sterilizable filters capable of preventing micro-
bial contamination of the contents. Such filters shall be designed and installed
so that they do not become wet. Filters shall be sterilized and installed aseptic-
ally. Tanks for holding water require air vents with filters [7,10].
E. Sanitization
Microbial control in water systems is achieved primarily through sanitization
practices. Systems can be sanitized using either thermal or chemical means. In-
line UV light can also be used to “sanitize” water in the system continuously.
1. Thermal Approaches
Thermal approaches to system sanitization include periodic or continuously cir-
culating hot water and the use of steam. These techniques are limited to systems
that are compatible with the higher temperatures needed to achieve sanitization,
such as stainless steel and some polymer formulations. Hot water circulation is
effective or essential for this purpose, especially for the WFI system.
2. Chemical Methods
Chemical methods, where compatible, can be used on a wider variety of con-
struction materials. These methods typically employ oxidizing agents such as
hypochlorite, hydrogen peroxide, ozone, or per-acetic acid. Hypochlorites are
effective sanitizers but are difficult to flush from the system and tend to leave
biofilms intact.
4. SIP/CIP
For a WFI or highly purified water system, the SIP/CIP method is usually ap-
plied. In an SIP/CIP system, sterilization and/or cleaning take in place in situ or
without dissembling the equipment. Consequently, the result of sterilization and/
or cleaning is confirmed by the process parameters previously validated. Based
on process parameters and their ranges previously determined by the process
validation, the SIP/CIP process can be confirmed whether or not it is completely
sterilized and cleaned. This is a typical application of the concept of validation.
F. Sampling Considerations
Water systems should be monitored at a frequency that is sufficient to ensure
that the system is in control and continues to produce water of acceptable qual-
ity. Samples should be taken from representative locations within the processing
and distribution system. Established sampling frequencies should be based on
system validation data and should cover critical areas. Unit operation sites might
be sampled less frequently than point-of-use sites. The sampling plan should
take into consideration the desired attributes of the water being sampled. Be-
cause of their more critical microbiological requirements, systems for WFI may
require a more rigorous sampling frequency.
When sampling water systems, special care should be taken to ensure that
the sample is representative. Sampling ports should be sanitized and thoroughly
flushed before a sample is taken. Samples for microbiological analysis should
4. Monitoring Program
Critical quality attributes and operating parameters should be documented and
monitored. The program may include a combination of in-line sensors or record-
ers (e.g., a conductivity meter and recorder), manual documentation of opera-
tional parameters (such as carbon filter pressure drop), and laboratory tests (e.g.,
total microbial counts). The frequency of sampling, the requirement for evaluat-
ing test results, and the necessity for initiating corrective action should be in-
cluded.
G. Microbial Considerations
The major exogenous source of microbial contamination is source or feed water.
At a minimum, feed water quality must meet the quality attributes of potable
water for which the level of coliforms is regulated. A wide variety of other
micro-organisms, chiefly gram-negative bacteria, may be present. These micro-
organisms may compromise subsequent purification steps. Examples of other
potential exogenous sources of microbial contamination include unprotected
vents, faulty air filters, backflow from contaminated outlets, drain air breaks,
and replacement activated carbon and deionizer resins. Sufficient care should
be given to system design and maintenance in order to minimize microbial con-
tamination from these sources.
Micro-organisms present in feed water may adsorb to carbon beds, deion-
izer resins, filter membranes, and other unit operation surfaces and initiate the
formation of a biofilm [2,8].
H. Endotoxin
Endotoxins are lipopolysaccharides from the cell envelope that is external to the
cell wall of gram-negative bacteria. Gram-negative bacteria readily form biofilm
that can become a source of endotoxin. Endotoxin may be associated with living
micro-organisms or fragments of dead micro-organisms, or may be free molecules.
The free form of endotoxin may be released from cell surfaces or biofilm that
colonize the water system, or they may enter the water system via the feed water.
Endotoxin should be eliminated by means of distillation, reverse osmosis,
and/or ultrafiltration. Generation of endotoxin is prevented by controlling the
I. Methodological Considerations
The objective of a water system microbiological monitoring program is to pro-
vide sufficient information to control the microbiological quality of the water
produced. An appropriate level of control may be maintained by using data
trending techniques and limiting specific contraindicated micro-organisms, con-
sequently it may not be necessary to detect all of the micro-organisms present.
The methods selected should be capable of isolating the numbers and types of
organisms that have been deemed significant relative to system control and
product impact for each individual system [2,8].
U.S. EEC/CGMP
Particles per Particles per m3 ISO classification of 209E USP 209E (1989)/WHO
m3 >0.1 µm ⭌ 0.5 µm airborne particulates (1992) customary GMP
— 1.00 —
102 3.50 ISO class 2 — — —
— 1.00 — M1 — —
103 35.30 ISO class 3 M1.5 1 —
— 102 — M2 —
104 3.53 × 102 ISO class 4 M2.5 10 —
— 103 — M3 — —
105 3.53 × 103 ISO class 5 M3.5 102 A&B
— 104 — M4 — —
106 3.53 × 104 ISO class 6 M4.5 103 —
— 105 — M5 — —
107 3.53 × 105 ISO class 7 M5.5 104 C
— 106 — M6 — —
108 3.53 × 106 ISO class 8 M6.5 105 D
— 107 — M7 —
冉 冊
2.08
0.1
Cn = 10N ×
D
where
1. Have hood or airflow direction panels and working surface areas that
are constructed of a smooth, durable, nonflaking material, such as
glass, plastic, or stainless steel.
2. Have prefilters that are disposable or fabricated from a material that
can be properly cleaned and reused.
3. Have HEPA final filters that have been tested to assure leak-proof
construction and installation.
4. Provide a laminar airflow with an average velocity of 90 ft per min
over the entire air exit area. The air velocity should be high enough
to maintain the unidirectional flow pattern.
5. Be monitored according to a written program and scheduled for com-
pliance with the requirements.
Schematic construction features for an aseptic processing area are shown
in Figure 7.
Terminally sterilized
Typical process step Not unusually at risk Unusually at risk Aseptically processed
Note. Capping and crimping, terminal sterilization, inspection and labeling and packaging “pharmaceuticals.”
a
For European aseptically produced products with sterile raw materials, where sterile filteration is not carried out,
then dispensing and compounding shall be in a grade A area, with a grade B background.
Source: Refs. 14, 20.
4. Air velocity
5. Airflow patterns
6. Air changes ratio
7. Pressure differentials
These parameters can affect the microbiological bioburden of the clean room.
Proper testing and optimization of the physical characteristics of the clean room
or controlled environment is essential prior to completion of the validation of
the microbiological monitoring program. Assurance that the controlled environ-
ment is operating adequately and according to its engineering specifications will
give a higher assurance that the bioburden of the environment will be appro-
priate for aseptic processing.
H. Training of Personnel
The major source of microbial contamination of controlled environments is per-
sonnel. Since the major threat of contamination of product being aseptically
processed comes from the operating personnel, the control of microbial contami-
nation associated with these personnel is one of the most important elements of
the environmental control program. Personnel training should be conducted be-
fore the qualification and validation practice [13].
20
VS = × 1000
Cn,m
where
When VS is very large, the time required for sampling can be substantial. By
using the sequential sampling procedure both the required sample volume and
the time required to obtain samples may be reduced.
The sampling probe shall be positioned pointing into the airflow. If the
direction of the airflow being sampled is not controlled or predictable (e.g.,
nonunidirectional airflow), the inlet of the sampling probe shall be directed ver-
tically upward. At a minimum, sample the above-determined volume of air at
each sampling location.
ceutical industry has been using microbial levels corresponding to air cleanliness
classes for a number of years, and these levels (shown in Table 5) have been
specified in various official compendia for evaluation of current GMP compliance
[13–16,19].
EU USP USP
(grade) ISO air class customary EU USP EU (55 m) (24–30 cm2) EU USP Descriptive
1. Barriers
In the context of aseptic processing systems, a barrier is a device that restricts
contact between operators and the aseptic field enclosed within the barrier. Bar-
riers may not be sterilized and do not always have transfer systems that allow
the passage of materials into or out of the system without exposure to the sur-
rounding environment. Barriers range from plastic curtains around the critical
production zones to rigid enclosures found on modern aseptic-filling equipment.
Barriers may also incorporate such elements as glove ports, half suits, and rapid-
transfer ports.